Chemical Synthesis of Tetracyclic Terpenes and Evaluation of Antagonistic Activity on Endothelin-A Receptors and Voltage-gated Calcium Channels

摘要

A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca²⁺ channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective reductive Robinson annulation was discovered for the formation of optically pure tricyclic terpenes. Stereoselective addition of cyanide to the hindered α-face of tetracyclic enone (-)->18 was found and subsequent transformation into the aldehyde function was affected by the formation of bicyclic hemiiminal (-)->4. Six selected synthetic tetracyclic terpenes show inhibitory activities in ET-1 induced vasoconstriction in the gerbil spiral modiolar artery with putative affinity constants ranging between 93 and 319 nM. Moreover, one compound, (-)->3, was evaluated further and found to inhibit voltage-activated Ca²⁺ currents but not to affect Na⁺ or K⁺ currents in dorsal root ganglion cells under similar concentrations. These observations imply a dual mechanism of action. In conclusion, tetracyclic terpenes represent a new class of hit molecules for the discovery of new drugs for the treatment of pulmonary hypertension and vascular related diseases.